2006
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EDITORIAL
The last issue of HTB this year – a double issue for November and December – includes a report from the latest BHIVA audit, together with reports from the recent Glasgow conference.
New i-Base book: “Why we must provide HIV treatment information”
i-Base has worked as a treatment literacy project for over six years. Over this time we have always produced copyright-free material and encouraged other organisations to use, translate and adapt our material. Through this work, we been very lucky to develop links to many other advocacy projects outside the UK.
CONFERENCE REPORTS:
Annual BHIVA Autumn conference,
13–14 October 2006, London.
- Causes of death in the UK: results from BHIVA audit
- Simon Collins, HIV i-Base
- The annual BHIVA audits are an essential mechanism for highlighting issues relating to management of HIV-positive patients in the UK. Over 130 clinics (80% from outside London), participate by providing information on an aspect of care. A wide range of clinics are involved: roughly 20% of participating clinics in this audit treat <50, 50-100, 101-200, 201-500 and >500 patients.
CONFERENCE REPORTS:
8th International Congress on Drug Therapy in HIV Infection,
12–16 November 2006, Glasgow
- d4T associated with significantly increased risk of type-2 diabetes mellitus
- Simon Collins, HIV i-Base
- The use of d4T (stavudine) has dramatically fallen in most Western countries, primarily due to high risk of lipoatrophy, and additive mitochondrial-related toxicity with other reverse transcriptase inhibitors. However, globally it remains one of the most widely ARVs prescribed first line therapy (in d4T/3TC/nevirapine), as the basis for the least expensive WHO-recommended fixed dose combinations (FDCs).
- Saquinavir/r vs. lopinavir/r: interim results from the Gemini study
- Simon Collins, HIV i-Base
- Results were presented in Glasgow by Slim and colleagues from a planned interim analysis of the first 150/337 treatment naïve patients randomised to either saquinavir/r (1000/100mg BID) of lopinavir/r (400/100mg BID) in a prospective openlabel study.
- Explanation for failure of TMC-125 (etravirine) in TMC227 study
- Simon Collins, HIV i-Base
- An oral presentation by Brian Woodfall provided an analysis of why Tibotec’s TMC227 study had performed so poorly. This trial was closed in November 2005 by the trial Data and Safety Monitoring Board (DSMB) because treatment-experienced patients in Thailand randomised to the new NNRTI etravirine (TMC-125) failed to show minimum -1 log virological response after 12 weeks.
- Wide disparity in switch to second-line therapy among children in CHIPS cohort
- Polly Clayden, HIV i-Base
- Kate Lee from the MRC presented data from the Collaborative HIV Paediatric Study (CHIPS) - a multicentre cohort of HIV positive children receiving care in 39 hospitals across the UK and Ireland since 1996. The CHIPS cohort includes 90% of HIV positive children in the UK and Ireland.
- Multi-drug resistance in vertically infected children
- Polly Clayden, HIV i-Base
- Vertically infected children are now surviving to adolescence and adulthood; in the CHIPS cohort the median age is now approaching 10 years.
- Viral load blips in children from the CHIPS cohort
- Polly Clayden, HIV i-Base
- A poster from CHIPS evaluated the characteristics, predictors and consequences of transient increases in viral load “blips” in children on HAART in the UK and Ireland.
- Switching from PIs to NNRTIs has similar effect on TC/HDL ratio as use of lipid lowering drugs in the management of dyslipidaemia
- Simon Collins, HIV i-Base
- Marc van der Valk presented an analysis comparing results from different approaches to the management of dyslipidaemia in an analysis from the D:A:D cohort. The study primarily looked at the different effect from using lipid lowering drugs (LLD) compared to switching from PI- to NNRTI-based regimens. This was informed by an earlier randomised study (Calza, AIDS 2005) that reported greater reductions in mean total cholesterol from baseline of -46% with pravastatin, and -38% with bezafibrate, compared to -27% and -10% after switching from a PI to either nevirapine or efavirenz respectively.
- Higher doses of ribavirin increases response rate to HCV treatment in coinfected patients: results from PRESCO study
- Simon Collins, HIV i-Base
- An oral presentation of the results from the PRESCO trial by Vincent Soriano was one of the most interesting late-breaker presentations in Glasgow. PRESCO used higher doses of ribavirin with pegylated interferon alfa-2a (180µg/week) in HCV coinfected patients, and was also designed to look at longer duration of HCV treatment.
- NNRTI levels high in HCV co-Infected patients with cirrhosis
- Mark Mascolini, for natap.org
- Plasma concentrations of non-nucleosides (NNRTIs) - especially nevirapine - proved high in hepatitis C virus (HCV)-coinfected patients with liver cirrhosis in a single-center Spanish study [1]. Cirrhosis did not affect protease inhibitor (PI) levels in this analysis.
- Drug interactions with darunavir (TMC-114)
- Simon Collins, HIV i-Base
- TMC114/r was studied with atazanavir (ATV), indinavir (IDV), lopinavir/r (LPV/r), saquinavir/r (SQV/r), efavirenz (EFV), nevirapine (NVP), tenofovir disoproxil fumarate (TDF), atorvastatin (AVS), omeprazole (OME), ranitidine (RAN), sildenafil (SIL), clarithromycin (CLA), sertraline (SER), paroxetine (PAR), oral contraceptives (OC) and ketoconazole (KTZ).
- Drug interactions with etravirine (TMC-125)
- Simon Collins, HIV i-Base
- Two-way PK interaction studies at steady-state were conducted with TMC125 and didanosine (ddI), tenofovir (TDF), the ritonavir (rtv)-boosted PIs darunavir (DRV), fosamprenavir (FPV) and tipranavir (TPV). The 1-way effect of omeprazole (OME) and ranitidine (RAN) on TMC125, and the 1-way effect of TMC125 on lopinavir (LPV) with saquinavir (SQV), methadone (MET) and sildenafil (SIL) were also studied.
- Community meeting on criminalisation of HIV transmission: jailing people for passing on HIV may threaten public health
- The conviction and imprisonment of people with HIV for transmitting their virus is counterproductive and may even threaten public health, the Eighth International Congress on Drug Therapy in HIV Infection was told this week. HIV criminalisation experts were addressing the conference’s community workshop, organised by the European AIDS Treatment Group.
ANTIRETROVIRALS
TREATMENT ACCESS
GUIDELINES
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- EDITORIAL
- As this issue went to press, named-patient programmes were about to start for both MK-0518 and TMC-125. Although he number of patients with multi-drug resistant HIV who are failing treatment is the UK is low - the 2006 BHIVA audit suggest that less than 3% of HIV-related deaths in the UK are related to lack of treatment options - for those patients these early access programmes clearly offer life-saving options.
- “Why we must provide HIV treatment information”
- Photography by Wolfgang Tillmans
- i-Base has worked as a treatment literacy project for over six years. Over this time we have always produced copyright-free material and encouraged other organisations to use, translate and adapt our material. Through this work, we been very lucky to develop links to many other advocacy projects outside the UK.
CONFERENCE REPORTS
- Introduction
- 23-26 September, San Francisco
- This annual Workshop is the most important meeting for researchers, clinicians and advocates who focus on metabolic complications relating to management of HIV-positive patients.
CONFERENCE REPORTS
CONFERENCE REPORTS
- Report from the 10th Annual UK Resistance Meeting
- Svilen Konov, HIV i-Base
- This year’s Annual UK Resistance Meeting was held on 21 September in London. Faculty were Professor Jonathan Weber, FRCP Imperial College, London and Dr Anna Maria Geretti from Royal Free Hospital, London.
CONFERENCE REPORTS
- Introduction
- 13-18 August 2006, Toronto, Canada
- In the September issue of HV Treatment Bulletin, we included first reports from this important meeting, including studies relating to treatment access, new antiretrovirals, treatment strategies including boosted PI-monotherapy, malignancies, basic science, some paediatric care and a range of other studies.
ANTIRETROVIRALS
- Early access programme for MK-0518 integrase inhibitor
- As this issue of HTB went to press, a named patient programme (NPP) for MK-0518, an integrase inhibitor currently in Phase 3 development by Merck, was due to be launched in the UK, with expected availability in the UK from late October. The programme is also called EARMRK and started in the US on 11 September 2006.
- Etravirine (TMC-125) available on named patient programme in the UK
- A named patient programme (NPP) will be available in the UK from 16 October 2006, for access to etravirine (TMC-125), a second-generation NNRTI currently in Phase 3 development by Tibotec.
- Fixed dose combination (FDC) of tenofovir/FTC/efavirenz (Atripla) filed in EU
- On 9 October 2006, filing for the fixed-dose combination of tenofovir/FTC/efavirenz (Atripla) was submitted to the European regulatory authorities (Committee for Medicinal Products for Human Use (CHMP), subject to validation by the EMEA). It usually takes approximately 6 months from filing for the EMEA to approve a Marketing Authorisation Application, and for the drug to become commercially available.
- Tipranavir available in Scotland - almost one year after EU approval
- Simon Collins, HIV i-Base
- A press release form Boehringer Ingelehiem on 11 September highlighted acceptance by the Scottish Medicines Consortium (SMC) for tipranavir/ritonavir in treatment experienced patients.
- FDA decision delayed on Biojector for administering T-20 pending additional safety information
- Simon Collins, HIV i-Base
- On 12 October, Roche issued a press release relating to the timeline for the FDA decision on the Biojector 2000 system that is currently being studied in an open label expanded access trial in the US.
TREATMENT ACCESS
- Gilead licenses tenofovir to Indian generic manufacturers
- On 22 September 2006, Gilead Sciences announced that it had signed new non-exclusive agreements with generic manufacturers in India, to produce and distribute generic versions of tenofovir disoproxil fumarate (tenofovir DF) to 95 low-income countries around the world, including India.
- FDA tentative approvals of generic ARVs
- Since the last issue of HTB, the US Food and Drug Administration (FDA) has granted tentative approval for the following new generic ARV products
- Funding prospects improve for Round 6 Global Fund
- Global Fund Observer
- At least $270 million will be available to finance Round 6 grants, and possibly as much as $620 million, according to recent estimates by the Global Fund.
GIUDELINES
- BHIVA draft report on UK standards for HIV care
- In preparing this report, now available for comment online, BHIVA has sought to produce a limited set of focused, auditable standards, which address key aspects of the organisation of NHS clinical care for adults with HIV infection. As such, this report is not intended as a comprehensive guide to good practice in HIV medicine. It should be read alongside BHIVA’s clinical guidelines and other relevant standards, recommendations and guidelines, including earlier standards developed by the Medical Foundation for AIDS and Sexual Health, which give a broader perspective on good practice.
- US adult treatment guidelines updated
- On October 10, 2006, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents released a new revision of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
TB COINFECTION
- Extensively drug resistant tuberculosis: A serious wake-up call for global health
- Editorial, BMJ
- Tuberculosis outbreaks in the developed world are newsworthy. [1] However, in the developing world, where deaths from tuberculosis are common, it takes something exceptional for an outbreak to attract much attention. In response to a recent report at the 16th international AIDS conference [2] and to increasing South African media reports, the World Health Organization last week expressed concern about extensively drug resistant tuberculosis (also referred to as “XDR tuberculosis”). [3]
- Global report on TB and HIV: new Analysis of TB/HIV epidemics in Bangladesh, Brazil, Nigeria, Tanzania, and Thailand
- A new report from the Public Health Watch project of the Open Society Institute (OSI), looks at the preventable but growing global TB epidemic, its interaction with HIV/AIDS, and the inadequate response to the two diseases in Bangladesh, Brazil, Nigeria, Tanzania, and Thailand. The study. Civil Society Perspectives on TB/HIV Policy, was released in August and is available online.
IMMUNOLOGY
- Viral load is a poor predictor of CD4 decline at the individual level
- Richard Jefferys, Treatment Action Group
- One of the more notorious quotes in the history of HIV research came from David Ho at an International AIDS Conference in 1994. During a presentation on the factors driving HIV pathogenesis, Ho put up a slide with the line “it’s the virus, stupid!” A study published in the journal Science in 1996 showing that viral load levels are a strong predictor of disease progression further solidified the view that there is a very direct connection between viral replication (as inferred by counting copies of HIV’s genetic material using viral load assays) and the development of immunodeficiency. [1]
- EDITORIAL
- This issue is focuses on reports form the XVI International AIDS Conference held in Toronto in August.
- “Why we must provide HIV treatment information”
- Photography by Wolfgang Tillmans
- i-Base has worked as a treatment literacy project for over six years. Over this time we have always produced copyright-free material and encouraged other organisations to use, translate and adapt our material. Through this work, we been very lucky to develop links to many other advocacy projects outside the UK.
CONFERENCE REPORTS
- 16th International AIDS Conference
- 13-18 August 2006, Toronto, Canada
- The XVI International AIDS Conference is the largest meeting of its kind. This year around 24,000 people traveled to Toronto to choose from over 4000 studies covering all aspects of HIV including basic science, clinical science, epidemiology, prevention, behavioural and policy-related research. It is organised every two years by the International AIDS Society (IAS) and since 2000 has alternated between northern and southern countries.
IAS : TREATMENT ACCESS
- Enough is enough: South African activists demand “fire Manto”
- Polly Clayden, HIV i-Base
- Throughout the conference activists from the Treatment Action Campaign (TAC) demanded that their government “Fire Manto” Dr Manto Tshabalala-Msimang, their nonsense-talking Minister of Health.
- Treatment access: more optimistic results from scale up programmes
- Simon Collins, HIV i-Base
- There were hundreds of posters relating to treatment access that were all very similar in describing successful results from roll-out programmes. All these studies are important. They document treatment success of local, regional or national significance, but contain few medical surprises. And as James McIntyre remarked in his rapporteur’s report: “In addition to large scale high impact access programmes thousands of smaller programmes are treating hundreds of thousands of people successfully at a community level.” What he called “the long tail of ART access”. [1]
IAS : NEW ANTIRETROVIRALS
- Integrase inhibitor MK-0518: early results show greater early potency than efavirenz
- Simon Collins, HIV i-Base
- The most exciting data at this meeting probably related to the late breaker from Merck, that presented limited 24-week data from a phase-II study of their integrase inhibitor MK-0518 in treatment-naive patients. [1]
- Maraviroc results in R5/X4 mixed/dual tropic patients: unexpected safety data shows possible immunolocical effect
- Simon Collins, HIV i-Base
- Of the three CCR5 inhibitors in development last year, only the Pfizer compound (maraviroc) is showing continued promise as a treatment for both naïve and treatment experienced patients. [1, 2]
- Vicriviroc 24-week results in triple-class experienced R5-tropic patients
- Mike Youle, for natap.org
- After the disappointment of earlier vicriviroc studies it was comforting to see some positive news with the late-breaker presentation by Trip Gulick of the ACTG5211 study assessing 3 doses of vicriviroc (VCV) against placebo in the highly experienced R5-tropic patient population.
- Etravirine (TMC-125) associated with -1 log viral load reduction at 48-weeks results in treatment experienced patients
- Simon Collins, HIV i-Base
- Cal Cohen from Community Research Initiative of New England, Boston reported 48-week results from the Tibotec randomised, controlled, Phase II study of etravirine (TMC-125) in 199 treatment experienced patients with documented NNRTI resistance and 3 or more primary PI mutations.
- Three-class experienced patients experience 1 log viral load reduction using monoclonal antibody TNX-355
- Simon Collins, HIV i-Base
- The late-breaker session also included a presentation of 48-week results from Tanox’s monoclonal antibody, TNX-355, in 82 triple-class experienced patients (87% male, 46% Causacian, mean age 46. [1]
- New data on darunavir (TMC-114)
- Mike Youle, natap.org
- Two posters in Toronto dealt with data for POWER 3 darunavir study. This is the follow-up study in treatment experienced patients, in which all subjects received TMC114/r 600/100mg from baseline, plus optimised background regimen (OBR).
IAS: TREATMENT STRATEGIES AND APPROVED ARVS
IAS: PAEDIATRIC STUDIES
IAS: MALIGNANCIES
- French study raises importance of early screening for anal cancer in HIV-positive people
- Simon Collins, HIV i-Base
- Christophe Piketty and colleagues looked at the impact of HAART on incidence of anal cancer diagnosed between 1992 and 2003 in HIV-positive patients from the French Database of HIV (FHDH). The analysis looked at pre-HAART, early HAART, and later HAART time periods. 92 cases were identified (84 men, 8 women) from almost 75,000 patients in the database.
- Prognostic index for risk of progression of Kaposi’s Sarcoma
- Simon Collins, HIV i-Base
- Mark Bower and colleagues from the Chelsea and Westminster Hospital London, presented a prognostic score for patients diagnosed with Kaposi’s Sarcoma (KS), derived from analysing covariates predictive of overall survival in a cohort of 326 HIV+ patients who developed KS since 1996.
- Tenofovir did not increase the incidence nephrotoxicity in limited numbers of HIV-positive patients using chemotherapy or HCV-coinfeced patients using ribavirin
- Simon Collins, HIV i-Base
- Two posters from the Chelsea and Westminster used their database of over 5,000 patients to look prospectively at patients using tenofovir in their ARV combination, who were also using potentially nephroptoxic chemotherapy for haematological malignancies, or retrospectively at HCV coinfected patients using ribavirin for HCV treatment.
IAS: BASIC SCIENCE
IAS: OTHER UK STUDIES
IAS: TREATMENT ACCESS & COMMUNITY RESPONSE
- Online webcasts and debates
- Many of the important sessions relating to healthcare policy and treatment access are available as webcasts, podcasts and transcriptions from kaisernetwork.org.
TREATMENT ACCESS
- Patent oppositions filed on three essential drugs
- In the continuing struggle to ensure that patents are not granted at the cost of human lives, health groups in India recently filed three more pre-grant patent oppositions against essential medicines.
WHO GIUDELINES
ANTIRETROVIRALS
ON THE WEB
- Online medical journals
- The “AIDS Issue” of the British medical journal The Lancet is now online at www.thelancet.com. Many of the articles are available for free, after registering on the site.
- Other resources
- As a resource for HIV-positive travelers, the German AIDS Federation and International Lesbian and Gay Association, have published an online overview of travel and entry restrictions in different countries: ‘Quick Reference: Travel and Residence Regulations for People with HIV and AIDS 2005’.
FUTURE MEETINGS
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EDITORIAL
This issue of HTB features reports from the XV International Drug Resistance workshop, held from 13-17 June in Sitges, Spain.
TREATMENT ALERT
CONFERENCE REPORTS
- Resistance implications of monotherapy with lopinavir/r (Kaletra)
- Simon Collins, HIV i-Base
- Virological and clinical responses from several small ritonavir-boosted PI monotherapy studies generated hope for the potential of simplified treatment irrespective of previous or concomitant nucleoside use. Of these, lopinavir/r has received most attention, as toxicity limited the use of indinavir/r monotherapy and potency is a concern for atazanavir/r monotherapy; but these studies were small (generally <20 patients), non-randomised and uncontrolled.
- Ritonavir reduces virological failure and resistance in treatment naïve patients treated with atazanavir
- Simon Collins, HIV i-Base
- Atazanavir was licensed in the US in June 2003 as a treatment for naïve or experienced patients, and in Europe it was licensed in March 2004 for use in treatment-experienced patients only. In practice, especially when once-daily combinations are important, and when there is a caution against using efavirenz, atazanavir is becoming used off-label in the UK as first line treatment. It’s lack of effect on lipids and good tolerability, also contributes to this use.
- Resistance to darunavir (TMC-114): predicting responses for treatment experienced patients
- Simon Collins, HIV i-Base
- As the drug closest to approval and the subject of much hope based on preliminary studies, it was appropriate that there were more individual posters relating to darunavir (TMC-114) than for other individual drugs (and mainly, but not all, were from Tibotec). With limited data from people who have failed on darunavir, several of the analyses reported below are preliminary, but also important. Darunavir was approved by the FDA on 23 June 2006.
- Epidemiological studies and transmission of resistance: evidence for optimism – or issues with interpretation?
- Simon Collins, HIV i-Base
- Trends in resistance, as expected, generally mirror changes in ARV use, with prevalence of PI-associated mutations dropping as NNRTI-based regimens became more widely used - and within class changes – generally reduction in TAMS and ddI-related mutations and an increase in K65R reflecting wider use of tenofovir. Similarly, D30N decreased and I50L increased reflecting lower use of nelfinavir and higher use of atazanavir. As usual, regional and national variations were reported among studies.
- K103N containing variants persist longer in women with subtype D and with higher viral loads
- Polly Clayden, HIV i-Base
- A group of women who had received single dose nevirapine in the HIVNET 012 trial were enrolled in a long-term (up to five years) follow-up study.
ANTIRETROVIRALS
- New formulation of lopinavir/r approved in Europe (Kaletra) and new tradename for access countries (Aluvia)
- On 3 July 2006 Abbott announced that it has received marketing authorisation from the European Commission for the Meltrex tablet formulation of lopinavir/ritonavir (Kaletra).
- U.S. approval for darunavir (TMC-114, Prezista)
- On 23 June 2006, the Food and Drug Administration (FDA), granted accelerated approval in the U.S. for darunavir (formerly TMC-114, tradename Prezista), for treatment experienced adults who are not responding to treatment with other antiretroviral drugs.
- Boehringer stops tipranavir trial in treatment-naïve patients
- On 13 June 2006, Boehringer Ingelheim announced that it was closing a clinical trial of HIV drug tipranavir (Aptivus) in treatment-naïve patients due to insufficient effectiveness at 60 weeks.
- FDA approves fixed-dose combination of efavirenz/tenofovir/FTC (Atripla): joint company collaboration produces once-daily one pill combination
- On 12 July 2006, the Food and Drug Administration (FDA) today approved Atripla, a new fixed-dose combination of three widely used antiretroviral drugs, to be taken in a single tablet once a day, alone or in combination with other ARVs. Atripla is the first fixed dose combination available in the United States to combine two different classes of antiviral drugs in a single pill. This “one-pill-once-a-day” product to treat HIV/AIDS combines the active ingredients of efavirenz (an NNRTI), with FTC (emtricitabine) and tenofovir DF (NRTIs). FTC and tenofovir are also available in a fixed dose combination (Truvada).
- Potential immunological advantage for CCR5: implications for inhibitors of this target
- Polly Clayden, HIV i-Base
- In second poster, authored by Mark Wainberg and coworkers, the same group presented findings from a study using a tissue culture based strategy to evaluate differences related to subtype and circulating recombinant forms (CRF) in the development of resistance in to TDF. [1]
TREATMENT ACCESS
- Activists meet with Gilead and Abbott over access to second-line therapy
- On 13-14 July, 25 activists from Africa, Asia, Latin America, the Caribbean, Eastern and Western Europe and the United States, met in London with two companies whose AIDS drugs are crucial in second-line regimens. Currently, patients in most developing countries and in many middle income countries have no treatment options if their first regimen fails due to resistance or side effects, because of the cost of second-line medicines.
- FDA approves four new generic products for use in PEPFAR
- In June 2006, the Food and Drug Administration (FDA) granted tentative approval for the following Indian generic products:
- List of current FDA approved generic formulations and products
- Simon Collins, HIV i-Base
- In June 2006, the Food and Drug Administration (FDA) granted tentative approval for the following Indian generic products:
- Data exclusivity: a new threat to affordable generic medicines
- Leena Menghaney, MSF
- The following information relates to the decision by the Indian government to amend the Drugs and Cosmetic Act, 1950. This is the act that protected the process a company invented to make a drug, but not the actual drug formulation itself, and which enabled some Indian generic manufacturers to produce chemically equivalent generic medicines at prices affordable to the developing world.
TREATMENT GUIDELINES
- Updated US perinatal guidelines
- The Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States has been revised to include an update of the “Antiretroviral Drug Resistance and Resistance Testing in Pregnancy” section to reflect new recommendations for resistance testing for HIV-infected pregnant women.
HEPATITIS COINFECTION
- Efficacy of treatment of acute hepatiitis C in patients with HIV-infection
- Simon Collins, HIV i-Base
- In a paper in the 13 May edition of AIDS, Stephanie Dominguez and colleagues reported impressive responses to treatment of hepatitis C in a prospective pilot study of 25 consecutive HIV-positive men from two clinic in Paris, with acute HCV infection (documented seroconversion to HCV antibody or positive HCV RNA with negative PCR in previous 6 months). [1]
CONFERENCE REPORTS
- Efavirenz levels above recommended upper target in 20% of African patients in Senegal
- Simon Collins, HIV i-Base
- Unusually for an African cohort, there was a majority of male participants in this study (86% male]. Earlier studies (Taylor et al) have suggested that higher efavirenz levels are more likely in African women than men, but this group did not report a gender difference.
- Lower dose of AZT provides adequate exposure in patients with low body weight
- Polly Clayden, HIV i-Base
- In Thailand, the standard AZT dose of 300 mg BD has frequently been linked with gastrointestinal intolerance and anaemia. Based on this observation, Thai National Guidelines recommend prescribing AZT at a dose of 200 mg BD in patients less than 60 kg. However, although some studies support AZT administration adjusted for body weight, 200 mg twice daily in patients less than 60 kg has never been formally evaluated.
- Pharmacokinetics for generic fixed dose combinations for children are comparable to the branded products
- Polly Clayden, HIV i-Base
- A small number of children are currently being treated with Pedimune within the CHAPAS 1 phase 1/2 trial in Zambia (sponsored by the MRC in London). This study will include evaluation of PK of nevirapine, d4T and 3TC in two daily paediatric doses of Pedimune in African children with and without malnutrition and in different age groups.
- Caution against dividing adult FDCs (Triomune) for young children
- Polly Clayden, HIV i-Base
- There are limited PK data on nevirapine in children treated with divided tablets and in whom malnourishment is common.
- University of Liverpool audit of paediatric TDM
- Polly Clayden, HIV i-Base
- Data from the Collaborative HIV Paediatric Study (CHIPS) Cohort - that includes 757 children in the UK and Ireland - show that 73% of HIV-positive children have received antiretroviral therapy. A previous CHIPS analysis has found that 40.5% children in this cohort had been under-dosed during their drug history
- Age-dependent pharmacokinetics of 3TC in children
- Polly Clayden, HIV i-Base
- The antiretroviral 3TC is licensed for treatment of HIV positive children from 3 months to 16 years. The recommended paediatric dose is 4mg/kg BD compared to the adult dose of 150mg BD (equivalent to 2mg/kg BD). The prescribing information from the originator company states: “Total exposure to lamivudine, as reflected by mean AUC values, was compatible between paediatric patients receiving an 8mg/kg/day dose and adults receiving a 4mg/kg/dose.”
- Use of small sample drug level monitoring for paediatric PI concentrations
- Polly Clayden, HIV i-Base
- A poster from J Lam and coworkers from the University of Southern California (USC), Pharmacology, Los Angeles, USA reported their methodology for total drug analysis from plasma with protein precipitation. This methodology simultaneously analyses multiple protease inhibitors in a single run, with a smaller injection volume, making it easier to use TDM, particularly in paediatrics, than previously published assays.
- Intracellular and plasma measurements of AZT and 3TC and their metabolites in neonates
- Polly Clayden, HIV i-Base
- Neonates receive antiretroviral prophylaxis often involving AZT either alone or in association with 3TC. Since access to intracellular NRTI triphosphate (TP) measurement is limited, pharmacological intracellular data are still lacking.
- Effect of pregnancy on PK of protease inhibitors
- Polly Clayden, HIV i-Base
- Previous studies investigating the PK of protease inhibitors show reduced exposure during pregnancy. M. Regazzi and coworkers from a multicentre cohort in Italy evaluated nelfinavir and lopinavir plasma levels in a group of HIV-positive pregnant women after receiving multiple doses.
- Using enzyme inducers to reduce the half-life of nevirapine
- Polly Clayden, HIV i-Base
- Several studies have reported the development of resistance to nevirapine even after taking a single dose of the drug, which is commonly used in the resource-limited setting for the prevention of mother to child transmission. This is likely due to the long half-life of nevirapine that results in the drug being found in blood for many days after taking the one dose.
- Relationship between nevirapine concentrations and virological failure in a clinical setting
- Polly Clayden, HIV i-Base
- Previous studies have reported high frequency of sub-optimal nevirapine Ctrough levels but no guidelines have suggested a way to manage these patients. Should a clinician confirm the inadequate concentration on another sample because of high intra-patient variability or increase nevirapine dose?
- Summary of drug interaction studies
- Simon Collins, HIV i-Base
- Several studies presented data on new drugs interactions. Some of these studies had been presented at earlier meetings, and the summary table of interactions from EACS, ICAAC and CROI, published in the April issue of HTB [1] may be a useful additional guide in association with those reported in the Table 1 below.
- Effects of ketoconazole and rifampin on TMC278
- Ben Cheng, HIV i-Base
- TMC-278 is a new non-nucleoside reverse transcriptase inhibitor in early stage clinical development. It had been previously reported that many of the commonly used HIV treatments and drugs used to treat and prevent opportunistic infections might interact with TMC-278.
- Brecanavir interaction study with ritonavir and atazanavir
- Ben Cheng, HIV i-Base
- Brecanavir is a new protease inhibitor that is currently in clinical studies and it is being studied in combination with low dose ritonavir. A drug interaction study involving 48 HIV-negative individuals participated in this study to evaluate the effects of atazanavir and ritonavir on brecanavir drug levels.
- Fixed-dose formulation of efavirenz/tenofovir/FTC bioequivalent to separate dosing
- Simon Collins, HIV i-Base
- A study by Mattias and colleagues from Gilead Sciences reported pharmacokinetic bioequivalence between the co-formulated fixed dose combination of efavirenz, tenofovir and FTC and plasma levels achieved when each drug was taken as single drug formulations.
- Saquinavir/r (1000/100mg) levels reduced when taken fasted and should be taken with food
- Simon Collins, HIV i-Base
- Marta Boffito and colleagues from the Chelsea and Westminster Hospital, compared absorption of saquinavir 500mg (dosed at 1000mg SQV with 100mg RTV, twice daily) when taken with a high calorie fat-containing meal (~1070kcal; 46-66g of fat), to when taken under fasted conditions.
- Lack of food effect with Meltrex formulation of lopinavir/r
- Simon Collins, HIV i-Base
- These studies were performed in HIV negative volunteers. As yet, there is no data from the Meltrex formulation in HIV-positive patients.
- Food interaction reduces ddI intracellular absorption and supports requirement to take fasted
- Simon Collins, HIV i-Base
- Girard and colleagues from St Antoine Hospital, Paris, presented data on intracellular (IC) levels of ddA-TP, the active metabolite of ddI, under fed and fasted conditions.
- Conflicting results on how T-20 affects tipranavir
- Mark Mascolini, for HIVpharmacology.com
- Two small cohort studies reached opposite conclusions on whether the fusion inhibitor enfuvirtide raises levels of the protease inhibitor tipranavir, and 7th HIV Pharmacology Workshop attendees could not sort out the discrepancy in an open discussion.
SPECIAL REPORTS
GUIDELINES
- US Adult Treatment Guidelines Updated
- The Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents was revised in May 2006.
- Draft BHIVA immunisation guidelines online
- Compared with HIV-seronegative individuals, HIV-seropositive persons may have an increased risk of infection or experience more severe disease following exposure to vaccine-preventable diseases. The positive impact of antiretroviral therapy on the natural history of HIV infection makes the formulation of HIV-specific immunisation guidelines important at this time.
TREATMENT ACCESS
- FDA tentative approval for generic abacavir
- Simon Collins, HIV i-Base
- On 18 May 2006, the Food and Drug Administration (FDA) granted tentative approval for a generic version of abacavir, manufactured by Aurobindo Pharma LTD. of Hyderabad, India.
- ITPC publish updated report on access to treatment
- In the week prior to the United Nations General Assembly Special Session on HIV/AIDS (UNGASS) the International Treatment Preparedness Coalition (ITPC) issued a report ‘Missing the Target – Off Target for 2010: How to Avoid Breaking the Promise of Universal Access’.
- Protesters evicted from UN headquarters, New York
- In the final hours of negotiations of the UN High-Level meeting on HIV/AIDS in New York this week, more than 100 civil society organisations worldwide staged an unprecedented protest shouting “The Declaration must include: treatment, targets, women and girls, harm reduction vulnerable groups”. As they were herded out from the hall by security guards they chanted “Silence is Death”.
- Community opposition filed against tenofovir patent application in India
- On 9 May 2006 the Indian Network for People Living with HIV/AIDS (INP+) and the Delhi Network of Positive People filed an opposition at the Delhi Patent Office to a patent application for tenofovir disoproxil fumarate (TDF).
RESISTANCE
- Web resources for HIV-1 genotypic-resistance test interpretation
- An article in the 15 April issue of Clinical Infectious Diseases, by Tommy Lui from US Division of Infectious Diseases, and and Robert Shafer from Stanford University, usefully describes the scientific principles of HIV-1 genotypic-resistance test interpretation and the most commonly used Web-based resources for clinicians ordering genotypic drug-resistance tests.
TB COINFECTION
SEXUALLY TRANSMITTED INFECTIONS
- LGV in the UK: almost 350 cases reported and still predominantly affecting HIV-positive gay men
- Michael Carter, aidsmap.com
- Over 300 cases of the sexually transmitted infection (STI) lymphogranuloma venereum (LGV) have been diagnosed in the United Kingdom, according to figures presented to a sexual health conference on May 10th. Nearly all the cases involved gay men, many of whom were HIV-positive. Co-infection with other sexually transmitted infections such as hepatitis C virus, was also common.
- EDITORIAL
- Included in this issue is Sir Liam Donaldson’s letter recommending PEP after non-occupational exposure as part of our national HIV prevention strategy in which he asks chief executives of all primary care trusts to “ensure that PEP is part of the spectrum of sexual health services for your local population.” We welcome this directive from the Department of Health but must reiterate our comment that this is more likely to have been driven by a legal challenge than by the recent publication of the BASHH guidelines on the use of PEPSE. The letter and guidelines must be widely publicised as (and we quote from a BHIVA presentation), “PEP can only work if people know about it.”
ERRATUM
PEP AFTER SEXUAL EXPOSURE: ACCESS IN THE UK
CONFERENCE REPORTS
- 12th Annual Conference of the British HIV Association
- 29 March–1 April 2006, Brighton
- The UK has approximately 60,000 people living with HIV, one-third of whom are undiagnosed, and around half of those diagnosed are on ARV treatment. Although, this is a relatively small number of people compared to many countries (<0.1% prevalence), the numbers of new diagnoses has increased for each of the last 3 years and was around 8,000 for 2005.
- Primary care practice still fails to diagnose HIV patients from high-risk groups or with symptomatic acute infection
- Simon Collins, HIV i-Base
- Fiona Burns from the Royal Free and UCL Medical School presented results form a survey of almost 290 recently diagnosed African patients, attending 14 London HIV clinics, between April 2004 and February 2006.
- Use of HLA B5701 genetic testing to reduce abacavir hypersensitivity reactions
- Simon Collins, HIV i-Base
- Several studies presented data relating to the use of the newly available HLA B5701 genetic test, which has the potential to identify people most at risk for abacavir-related hypsersensitivity reactions (HSR).
- Dosing rifabutin and lopinavir/r – sub-optimal rifabutin levels reported in five patients dosed according to current guidelines
- Simon Collins, HIV i-Base
- Hasanin Khachi and colleagues from Barts and the London Trust reported drug levels of rifabutin in five patients concurrently using lopinavir/r-based ARV regimens. Following current guidelines (BHIVA, CDC), rifabutin dose was reduced from 300mg daily to 150mg three times a week, in five patients, and levels were measured using standard therapeutic drug monitoring after two weeks.
- Fatal seronegative visceral leishmaniasis in Portuguese patient
- Simon Collins, HIV i-Base
- Andrew Benzie and colleagues from St Mary’s reported the case of a 38 year old, ARV-naive Portuguese man, who presented in April 2005, with a 6-month history of intermittent episodes of high fever, dry cough and shortness of breath on exertion, which increased in severity with each episode.
- Awareness of PEP after sexual exposure (PEPSE)
- Simon Collins, HIV i-Base
- Andrew Benzie and colleagues from St Mary’s reported the case of a 38 year old, ARV-naive Portuguese man, who presented in April 2005, with a 6-month history of intermittent episodes of high fever, dry cough and Shamela de Silva and colleagues reported the results of a prospective questionnaire completed by 88/100 men attending walk-in GU services and 83/100 HIV-positive men attending St Mary’s HIV clinic. of breath on exertion, which increased in severity with each episode.
CONFERENCE REPORTS
CROI: RESOURCE LIMITED SETTINGS
- Regimen durability and toxicity in 36-month follow up on ART in Khayelitsha, South Africa
- Polly Clayden, HIV i-Base
- Andrew Boulle from the University of Cape Town, presented findings from 36-months of follow up of the Médecins Sans Frontières and Provincial Government programme in Khayelitsha, South Africa.
- Adults in resource-limited settings are most likely to experience an HIV-associated Illness in the first three months from initiating therapy
- Polly Clayden, HIV i-Base
- Programmes in resource-limited settings have reported relatively high mortality rates following initiation of therapy, particularly in the first few months.
- Causes of death in adults receiving ARV therapy in Senegal
- Polly Clayden, HIV i-Base
- Eric Delaporte from the University of Montpelier presented findings from a ANRS study to evaluate survival and causes of death among HIV positive adults receiving ART in Senegal.
- Rapid scale-up of treatment in Zambia delivered at primary health level
- Polly Clayden, HIV i-Base
- Scale up of HIV care and treatment services is currently underway in a number of developing countries. In an oral presentation Moses Sinkala from the Zambian Ministry of Health reported on programmatic outcomes from 18 public and private clinical sites across the Lusaka area of Zambia.
- The effect of HIV subtype on disease progression in Rakai, Uganda
- Polly Clayden, HIV i-Base
- Previous Ugandan studies have found more rapid disease progression in people with subtype D than with subtype A.
CROI: WOMEN’S HEALTH
- Genital tract pharmacokinetics of ten antiretroviral drugs in HIV-positive women
- Polly Clayden, HIV i-Base
- A poster authored by Julie Dumond and coworkers from the University of North Carolina evaluated first dose and steady state pharmacokinetics of 10 antiretrovirals (ARVs) in the female genital tract. The authors explained: “ARVs rapidly achieving high genital tract concentrations may be targets for optimal PREP and PEP.”
- ARV treatments rapidly reduces cervical and vaginal HIV-1 RNA
- Polly Clayden, HIV i-Base
- Decreased genital HIV-1 RNA shedding in women is associated with lower risk of both mother to child transmission and probably heterosexual transmission. A poster by Susan Graham and coworkers reported findings from an evaluation of genital HIV-1 RNA shedding in women in women initiating antiretroviral therapy.
- Effect of HSV-2 treatment on HIV-1 genital shedding and plasma viral load
- Polly Clayden, HIV i-Base
- Previous epidemiological data have suggested that herpes simplex virus 2 (HSV-2) infection can increase HIV-1 genital shedding, and in turn increase HIV-1 transmissibility among coinfected people. To date this causal relationship has never been demonstrated.
CROI: PAEDIATRIC STUDIES
- Once-daily FTC, ddI, and efavirenz in children and adolescents
- Polly Clayden, HIV i-Base
- Easy to take once a day regimens seem particularly desirable for paediatric HIV treatment, both for children and their caregivers. It is expected that a once a day strategy will improve adherence and, in turn, efficacy.
- Simplified triple NRTI regimen effective in vertically infected children: two years follow-up
- Polly Clayden, HIV i-Base
- Guido Castelli-Gattinara from Bambino Gesu hospital in Rome presented findings from a study evaluating a switch from protease based HAART to a simplified triple nucleoside regimen in a group of 20 vertically infected children.
- Long-term clinical and biological outcomes in children vertically infected with HIV
- Polly Clayden, HIV i-Base
- Few clinical and biological data are available for adolescents living with HIV since birth.
- Prospective follow up of children with lipodystrophy
- Polly Clayden, HIV i-Base
- There are limited prospective data on lipodystrophy in HIV positive children, particularly with regard to the changes that take place during puberty, and the prognostic value and clinical significance of the different types of fat redistribution and lipid/glucose abnormalities [1].
- Tuberculosis in HIV-infected children often missed from incidence data: the influence of HAART on paediatric TB
- Polly Clayden, HIV i-Base
- In the developing world, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV positive children.
- Nevirapine pharmacokinetics with infant prophylaxis
- Polly Clayden, HIV i-Base
- In infants whose mothers receive no antiretroviral treatment or mother to child transmission (MTCT) prophylaxis during pregnancy, the optimal composition and duration of postnatal antiretroviral prophylaxis to prevent transmission is unknown.
CROI: TRANSMISSION & PREVENTION
- Prevention of rectal transmission of SIV in macaques using FTC with tenofovir: FTC has independent protective effect even as monotherapy
- Simon Collins, HIV i-Base
- Walid Heneine from CDC Atlanta, presented results showing that adding FTC to tenofovir provided greater protection against SIV infection that standard dose tenofovir. A separate study with FTC monotherapy found an independent protective effect.
- K65R frequently emerges within 1-6 weeks of tenofovir monotherapy in macaques
- Simon Collins, HIV i-Base
- Jeffrey Johnson and colleagues from CDC Atlanta and the University of California performed longitudinal resistance tests on plasma sample from eleven SIV-infected macaques, receiving 30mg/kg tenofovir daily using a test sensitive to 0.2% mutant virus.
- A genome armed against HIV
- David Margolis, for natap.org
- Steve O’Brien of the NCI reviewed the understanding gained by his group and others over the past decade on human genes which either reduce or increase the transmission of HIV and the progression of HIV infection to AIDS.
- Circumcision: a surprising benefit from an unkind cut
- David Margolis, for natap.org
- Tom Quinn of Hopkins and the NIAID reviewed the maturing data that show that male circumcision confers protection against HIV infection. The biological basis for the protective effect of circumcision is not clear, but the foreskin is not keratinised and heavily enriched in dendritic cells, making it a potentially advantageous entry site for the virus. Quinn reported a number of epidemiological facts that suggested circumcision protects against HIV infection
- Topical microbicides: the real front line of HIV prevention
- David Margolis, for natap.org
- Topical microbicides, preparations able to kill HIV on contact and prevent infection, are a critical complement to vaccines and other prevention strategies. They can protect women, for example, who cannot protect themselves by other means. Gels are in development and testing, but a plan is needed for future approaches if the results of trials expected in 2006-07 are not encouraging.
CONFERENCE REPORTS: 13th Conference on Retroviruses and Opportunistic Infections (CROI), 5-8 February 2006, Denver
CROI: ANTIRETROVIRALS
CROI: TREATMENT STRATEGIES
- Simplification to atazanavir/ritonavir monotherapy
- Simon Collins, HIV i-Base
- Susan Swindells and colleagues from University of Nebraska presented results from a study that switched 36 patients who had suppressed viral load <50 copies/mL for at least one year on their first PI-based triple therapy (with 2 RTIs), to atazanavir/ritonavir maintenance therapy. The primary endpoint of the study was viral suppression <200 copies/mL at 24 weeks after stopping the RTIs.
CONFERENCE REPORT
- Rifaximin cure reported for cryptosporidium in advanced HIV
- Simon Collins, HIV i-Base
- Rifaximin (Xifaxin) is a rifamycin marketed by Salix, with an indication for treatment for travellers diarrhoea caused by noninvasive strains
of Escherichia coli. Although only approved in the US in May 2004, it has been available in Europe for many years. Several posters at
ICAAC referred to ongoing research with rifaximin as a treatment for for clostridium difficile.
- Analysis of hepatic events in 2NN study by CD4 entry criteria, levels differences between nevirapine and efavirenz; excess hepatic events in once-daily nevirapine arm linked to single site in Thailand
- Simon Collins, HIV i-Base
- Baseline median characteristics included CD4 cell count just below 200 cells/mm3 [range 70-330] and plasma viral load of 4.7 log [4.4-5.5]). One of the key findings showed a higher rate of hepatobilary lab toxicity in the nevirapine once-daily compared to the twice-daily arm (13.2 vs 7.8, p=0.002), despite similar efficacy. The results, presented at the Retrovirus conference in February 2003, provided key comparative data for how NNRTIs have subsequently been used in clinical practice.
- FTC studies at EACS: reduced incidence of M184V compared to 3TC; side effect profile in clinical practice
- Simon Collins, HIV i-Base
- After a relatively long and low profile development, FTC (emtricitabine) was licensed in Europe in October 2003. It quickly became included in UK and US treatment guidelines as a drug that is interchangeable with 3TC (lamivudine), with which it shares a similar chemical structure and resistance pattern.
- Paediatric studies at EACS
- Polly Clayden, HIV i-Base
- As of July 2005, the median age of the children was 13 years (range: 1-23 years). Their median CD4 nadir was 15% (IQR: 6-23%). Of the group 83% of children were receiving HAART, 5% were still receiving dual therapy and 12% were untreated. Of children receiving HAART, 29% were on their first antiretroviral regimen, 36% their second and 34% on their third or more regimen. Overall, the median CD4 percentage was 31% (IQR: 25-37%) and 57% of the group had a viral load of <400 copies/mL.
- Efficacy of lopinavir/r in patients with advanced HIV (CD4 <25 cells/mm3)
- Simon Collins, HIV i-Base
- An analysis from four randomised studies of lopinavir/r, that stratified patients by baseline CD4, showed that comparable results were achieved by patients even with the most advanced HIV defined as CD4 counts <25 cells/mm3 and/or viral load >300,000 copies/mL (comprising 11% and 21% of the pooled study populations respectively).
- Factors associated with sexual dysfunction in HIV patients
- Svilen Konov, HIV i-Base
- A prospective study, started in 2000, followed 279 HIV-infected patients, in an attempt to discover the reasons behind sexual dysfunction. [1] The data have been obtained via semi-structured interviews and DSM-IV criteria were used to categorise the sexual alterations. Likert scales were used to grade the patient nformation related to their own treatment.
This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1980-2006. AEGiS.